Journey of Trail From Bench to Bedside and Its Potential Role in Immuno-Oncology

Induction of apoptosis in cancer cells has increasingly been the focus of many therapeutic approaches in oncology field. Since its identification as a TNF family member, TRAIL (TNF-related apoptosis-inducing ligand) paved a new path in apoptosis inducing cancer therapies. Its selective ability to activate extrinsic and intrinsic cell death pathways in cancer cells only, independently from p53 mutations responsible for conventional therapeutics resistance, spotted TRAIL as a potent cancer apoptotic agent. Many recombinant preparations of TRAIL and death receptor targeting monoclonal antibodies have been developed and being tested pre-clinically and clinically both as a single agent and in combinations. Of note, the monoclonal antibodies were not the only type of antibodies developed to target TRAIL receptors. Recent technology has brought forth several single chain variable domains (scFv) designs fused recombinantly to TRAIL as well. Also, it is becoming progressively more understandable that field of nanotechnology has revolutionized cancer diagnosis and therapy. The recent breakthroughs in materials science and protein engineering have helped considerably in strategically loading drugs into nanoparticles or conjugating drugs to their surface. In this review we aim to comprehensively highlight the molecular knowledge of TRAIL in the context of its pathway, receptors and resistance factors. We also aim to review the clinical trials that have been done using TRAIL based therapies and to review various scFv designs, the arsenal of nano-carriers and molecules available to selectively target tumor cells with TRAIL

Role of Nanotechnology and Gene Delivery Systems in TRAIL-Based Therapies

Since its identification as a member of the tumour necrosis factor (TNF) family, TRAIL (TNF-related apoptosis-inducing ligand) has emerged as a new avenue in apoptosis-inducing cancer therapies. Its ability to circumvent the chemoresistance of conventional therapeutics and to interact with cancer stem cells (CSCs) self-renewal pathways, amplified its potential as a cancer apoptotic agent. Many recombinant preparations of this death ligand and monoclonal antibodies targeting its death receptors have been tested in monotherapy and combinational clinical trials. Gene therapy is a new approach for cancer treatment which implies viral or non-viral functional transgene induction of apoptosis in cancer cells or repair of the underlying genetic abnormality on a molecular level. The role of this approach in overcoming the traditional barriers of radiation and chemotherapeutics systemic toxicity, risk of recurrence, and metastasis made it a promising platform for cancer treatment. The recent first Food Drug Administration (FDA) approved oncolytic herpes virus for melanoma treatment brings forth the potency of the cancer gene therapy approach in the future. Many gene delivery systems have been studied for intratumoural TRAIL gene delivery alone or in combination with chemotherapeutic agents to produce synergistic cancer cytotoxicity. However, there still remain many obstacles to be conquered for this different gene delivery systems. Nanomedicine on the other hand offers a new frontier for clinical trials and biomedical research. The FDA approved nanodrugs motivates horizon exploration for other nanoscale designed particles\u27 implications in gene delivery. In this review we aim to highlight the molecular role of TRAIL in apoptosis and interaction with cancer stem cells (CSCs) self-renewal pathways. Finally, we also aim to discuss the different roles of gene delivery systems, mesenchymal cells, and nanotechnology designs in TRAIL gene delivery

Novel targeted therapies and immunotherapy for advanced thyroid cancers

Thyroid cancer is a frequently encountered endocrine malignancy. Despite the favorable prognosis of this disease, 15–20% of differentiated thyroid cancer (DTC) cases and most anaplastic types, remain resistant to standard treatment options, including radioactive iodine (RAI). In addition, around 30% of medullary thyroid cancer (MTC) cases show resistance after surgery. The evolving understanding of disease-specific molecular therapeutic targets has led to the approval of two targeted therapies (Sorafenib and Lenvatinib) for RAI refractory DTC and another two drugs (Vandetanib and Cabozantinib) for MTC. These advanced therapies exert their effects by blocking the MAPK pathway, which has been widely correlated to different types of thyroid cancers. While these drugs remain reserved for thyroid cancer patients who failed all treatment options, their ability to improve patients’ overall survival remain hindered by their low efficacy and other molecular factors. Among these factors is the tumor’s ability to activate parallel proliferative signaling pathways other than the cascades blocked by these drugs, along with overexpression of some tyrosine kinase receptors (TKR). These facts urge the search for novel different treatment strategies for advanced thyroid cases beyond these drugs. Furthermore, the growing knowledge of the dynamic immune system interaction with tumor microenvironment has revolutionized the cancer immune therapy field. In this review, we aim to discuss the molecular escape mechanisms of thyroid tumors from these drugs. We also highlight novel therapeutic options targeting other pathways than MAPK, including PI3K pathway, ALK translocations and HER2/3 receptors and their clinical impact. We also aim to discuss the usage of targeted therapy in restoring thyroid tumor sensitivity to RAI, and finally turn to extensively discuss the role of immunotherapy as a potential alternative treatment option for advanced thyroid diseases. Electronic supplementary material The online version of this article (10.1186/s12943-018-0786-0) contains supplementary material, which is available to authorized users

Cracking and Fiber Debonding Identification of Concrete Deep Beams Reinforced with C-FRP Ropes against Shear Using a Real-Time Monitoring System

Traditional methods for estimating structural deterioration are generally costly and inefficient. Recent studies have demonstrated that implementing a network of piezoelectric transducers mounted to critical regions of concrete structural members substantially increases the efficacy of the structural health monitoring (SHM) method. This study uses a recently developed electro-mechanical-admittance (EMA)-based SHM system for real-time damage diagnosis of carbon FRP (C-FRP) ropes installed as shear composite reinforcement in RC deep beams. The applied SHM technique uses the frequency response measurements of a network of piezoelectric lead zirconate titanate (PZT) patches. The proposed strengthening methods using C-FRP ropes as ETS and NSM shear reinforcement and the applied anchorage techniques significantly enhanced the strength and the overall performance of the examined beams. The retrofitted beams exhibited increased shear capacity and improved post-peak response with substantial ductility compared with the brittle failure of the non-strengthened specimens. The health condition and the potential debonding failure of the applied composite fiber material were also examined and quantified using the proposed SHM technique. Damage quantification of C-FRP ropes is achieved by comparing and assessing the values of several statistical damage indices. The experimental results demonstrated that the proposed monitoring system successfully diagnosed the region where the damage occurred by providing early warning of the forthcoming critical shear cracking of concrete and C-FRP rope debonding failures. Furthermore, the internal PZT transducers showed sound indications of the C-FRP rope’s health condition, demonstrating a direct correlation with the mechanical performance of the fibers

An Electromechanical Impedance-Based Application of Realtime Monitoring for the Load-Induced Flexural Stress and Damage in Fiber-Reinforced Concrete

Effective real-time structural health monitoring in concrete structures is paramount to evaluating safety conditions and the timely maintenance of concrete structures. Especially, the presence of discrete fibers in fiber-reinforced concrete restrains crack propagation into small and thin cracks, which increases the difficulty in detecting damage. In this study, an array of piezoelectric lead zirconate titanate (PZT) transducers was applied to study the effects of external load-induced flexural stress and damage in fiber-reinforced concrete beams using the electromechanical impedance (EMI) or electromechanical admittance (EMA) methods. Beams were subjected to a four-point bending test under repeatable loading, while PZTs evaluated corresponding flexural stress and induced damage simultaneously. Due to the influence of the medium’s stress fields in the different types of wave propagation in structural elements, PZT transducers measurements are accordingly affected under variable stress fields, in addition to the effect of the higher level of damage that occurred in the medium. According to the results of the tests, variation in EMA signatures, following flexural stress and gradual damage changes, provided convincing evidence for predicting stress and damage development

Fiber Reinforced Polymer Debonding Failure Identification Using Smart Materials in Strengthened T-Shaped Reinforced Concrete Beams

The favorable contribution of externally bonded fiber-reinforced polymer (EB-FRP) sheets to the shear strengthening of reinforced concrete (RC) beams is widely acknowledged. Nonetheless, the premature debonding of EB-FRP materials remains a limitation for widespread on-site application. Once debonding appears, it is highly likely that brittle failure will occur in the strengthened RC structural member; therefore, it is essential to be alerted of the debonding incident immediately and to intervene. This may not be always possible, particularly if the EB-FRP strengthened RC member is located in an inaccessible area for fast inspection, such as bridge piers. The ability to identify debonding immediately via remote control would contribute to the safer application of the technique by eliminating the negative outcomes of debonding. The current investigation involves the detection of EB-FRP sheet debonding using a remotely controlled electromechanical admittance (EMA)-based structural health monitoring (SHM) system that utilizes piezoelectric lead zirconate titanate (PZT) sensors. An experimental investigation on RC T-beams strengthened for shear with EB-FRP sheets has been performed. The PZT sensors are installed at various locations on the surface of the EB-FRP sheets to evaluate the SHM system’s ability to detect debonding. Additionally, strain gauges were attached on the surface of the EB-FRP sheets near the PZT sensors to monitor the deformation of the FRP and draw useful conclusions through comparison of the results to the wave-based data provided by the PZT sensors. The experimental results indicate that although EB-FRP sheets increase the shear resistance of the RC T-beams, premature failure occurs due to sheet debonding. The applied SHM system can sufficiently identify the debonding in real-time and appears to be feasible for on-site applications

Signaling cascades in thyroid cancer: Increasing the armory of archers to hit bullseye

Thyroid cancer is a multifaceted and therapeutically challenging disease and rapidly accumulating experimentally verified findings have considerably improve our understanding of the molecular mechanisms which underlie its development. Substantial fraction of information has been added into existing landscape of molecular oncology and we have started to develop a sharper understanding of the underlying mechanisms of thyroid cancer. Wealth of information demystified different intracellular signaling cascades which are frequently deregulated in thyroid cancer. In vitro assays and xenografted mice based studies have helped us to identify drug targets and different synthetic and natural products are currently being tested to effectively treat thyroid cancer. Cabozantinib and vandetanib have been approved to treat medullary thyroid cancer (MTC) and two agents (lenvatinib and sorafenib) are also being used to treat radioactive-iodine refractory differentiated thyroid cancer. This review comprehensively summarizes most recent advancements in our knowledge related to dysregulated intracellular signaling cascades in thyroid cancer and how different proteins can be therapeutically exploited. (1) We discuss how loss of TRAIL mediated apoptosis occurred in thyroid cancer cells and how different strategies can be used to restore apoptosis in resistant cancer cells; (2) We provide detailed account of seemingly opposite roles of NOTCH signaling in thyroid cancers; (3) TGF/SMAD mediated signaling also needs detailed research because of context dependent role in thyroid cancer. Researchers have only begun to scratch the surface of how TGF signaling works in thyroid cancer and metastasis; and (4) Role of SHH signaling in thyroid cancer stem cells is also well appreciated and targeting of SHH pathway will be an important aspect in treatment of thyroid cancer. Better concepts and improved knowledge will be helpful for clinicians in getting a step closer to individualized medicine

Signaling cascades in thyroid cancer: Increasing the armory of archers to hit bullseye

Thyroid cancer is a multifaceted and therapeutically challenging disease and rapidly accumulating experimentally verified findings have considerably improve our understanding of the molecular mechanisms which underlie its development. Substantial fraction of information has been added into existing landscape of molecular oncology and we have started to develop a sharper understanding of the underlying mechanisms of thyroid cancer. Wealth of information demystified different intracellular signaling cascades which are frequently deregulated in thyroid cancer. In vitro assays and xenografted mice based studies have helped us to identify drug targets and different synthetic and natural products are currently being tested to effectively treat thyroid cancer. Cabozantinib and vandetanib have been approved to treat medullary thyroid cancer (MTC) and two agents (lenvatinib and sorafenib) are also being used to treat radioactive-iodine refractory differentiated thyroid cancer. This review comprehensively summarizes most recent advancements in our knowledge related to dysregulated intracellular signaling cascades in thyroid cancer and how different proteins can be therapeutically exploited. (1) We discuss how loss of TRAIL mediated apoptosis occurred in thyroid cancer cells and how different strategies can be used to restore apoptosis in resistant cancer cells; (2) We provide detailed account of seemingly opposite roles of NOTCH signaling in thyroid cancers; (3) TGF/SMAD mediated signaling also needs detailed research because of context dependent role in thyroid cancer. Researchers have only begun to scratch the surface of how TGF signaling works in thyroid cancer and metastasis; and (4) Role of SHH signaling in thyroid cancer stem cells is also well appreciated and targeting of SHH pathway will be an important aspect in treatment of thyroid cancer. Better concepts and improved knowledge will be helpful for clinicians in getting a step closer to individualized medicine